We are following 50,844 US and Puerto Rican women who were between the ages of 35 and 74 and had a sister with breast cancer but did not have breast cancer themselves when they joined the study between 2003 and 2009. At enrollment, data on potential risk factors and current health status were collected using computer assisted telephone interviews and mailed questionnaires. Blood, urine, and environmental samples were collected in a home visit and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort is tracked annually for changes in vital status and major health outcomes. Detailed follow-up questionnaires on health outcomes, environmental and lifestyle exposures, and special topics are completed every 2-3 years. Medical records and tumor tissue (for breast cancer cases) are retrieved for those who develop cancer or other conditions of interest. The first Sister Study follow-up survey was completed in June 2012; responses were obtained from 48,090 women for a response rate of 95%. The second detailed follow-up (January 2012 to 2014) has been completed with better than 90% response. The third comprehensive follow-up is underway. We recently collected biological and environmental samples from women diagnosed with breast cancer since enrollment and a random sample of the cohort. This will allow us to explore changes in biomarkers and exposures over time and in relation to breast cancer diagnosis and treatment. More than 2,000 women have reported a diagnosis of breast cancer or DCIS/LCIS. As expected, women in the cohort have, on average, twice the breast cancer risk as other US women. The ratio of observed to expected cases is greatest for women who also have a mother with breast cancer and for those whose sisters were younger at diagnosis. A novel finding is that risk differs for women with maternal versus paternal family history. All breast cancer and ovarian cancer cases and a random sample of the cohort have been genotyped as part of the multi-study Oncoarray project. We will also have data on 450,000 CpGs for the same 2000 breast cancer cases and 2000 non cases to evaluate methylation patterns in relation to breast cancer and in relation to exposures of interest. In a study of urinary prostaglandin E2-metabolite (PGE-M) in 609 post-menopausal women (301 breast cancer cases and 308 subcohort members), several known pro- and anti-inflammatory factors were associated with urinary PGE-M, and post-menopausal breast cancer risk was increased with increasing levels of urinary PGE-M among women who did not regularly use non-steroidal anti-inflammatory drugs (NSAIDs). A related paper on fruit and vegetable intake is under review. These results support a role for prostaglandin E2 and inflammation in breast carcinogenesis, which may be modifiable by lifestyle and pharmacological interventions. We evaluated whether women at high risk for breast cancer were appropriately receiving tamoxifen therapy and explored factors associated with uptake and discontinuation of this treatment and found both under and over-use of this treatment in specific subgroups. In an analysis of occupational exposures, we found that occupational solvent exposure was associated with increased risk for estrogen-receptor positive breast cancer and that risk was greatest for women exposed before a first full-term pregnancy a period of potentially enhanced susceptibility in breast tissue development. We also reported suggestive associations with use of potentially endocrine disrupting chemicals and found a potentially protective effect of occupational physical activity. We confirmed a previously reported link between increasing body mass index (one measure of obesity) and post-menopausal breast cancer risk and found that central adiposity (as measured by waist circumference) was associated with risk for both pre- and post-menopausal breast cancer. With co-investigators at the University of Washington, we geocoded participant addresses and linked these to information on air pollution levels. We reported associations between ambient air pollution and risk for asthma and hypertension and recently found that while there was no overall link between air pollution and breast cancer, air pollution was associated with increased risk for hormone receptor positive breast cancer in this cohort. The Sister Study is collaborating with researchers from the Division of Cancer Prevention and Control at the Centers for Disease Control and Prevention (CDC) to study quality of life in breast cancer survivors. A survey of approximately 20,000 Sister Study participants in 2012 focused on the impact of having a sister with breast cancer. A second survey, completed in May 2013, involved women diagnosed with breast cancer and included topics that are of particular interest to younger women such as body image, work-life balance, and fertility as well as questions related to breast cancer care and quality of life. Together, these surveys will increase our understanding of the impact of cancer on the lives of breast cancer survivors and their families and provide information that will help identify factors related to healthy living after diagnosis. Current analyses focus on receipt of and satisfaction with prophylactic mastectomy, whether breast MRI is being used appropriately for high risk women, neurocognitive symptoms following chemotherapy, and behavioral change following breast cancer diagnosis. The Sister Study participates in the NCI-sponsored Cohort Consortium and has contributed cases a and data to studies of head and neck, gallbladder and ovarian cancers, allowing us to contribute to research on conditions we are not able to address on our own due to sample size constraints. We are taking the lead on a new Consortium project on pregnancy-associated breast cancer and co-directing a Consortium study on risk factors for pre-menopausal breast cancer. To date 19 cohorts have joined this effort.